This Program Project represents a coordinated and mutually supporting effort to pursue research in structural biology where electron diffraction and electron microscopy play a key role and to advance the technology that enables this research. Three projects within the Program represent applications of the methods of electron crystallography and microscopy, as well as of the instrumentation supported by the Program, to specific problems in structural biology. These applications focus on aspects of the eukaryotic cytoskeleton and include: (Project A) Studies of the structure of tubulin and its interactions with ligands and other proteins that affect the function of the microtubule cytoskeleton; (Project B) Studies of the apparatus in the inner ear that converts sound to nerve signals and controls sensitivity of hearing; (Project C) Studies of the proteins that connect microtubules to chromosomes and ensure proper chromosome segregation during cell division. Additional, separately funded research projects which rely to a smaller extent on equipment and facilities supported by the Program Project are also included as Associate member projects. The Administrative Core (Project D) maintains the major equipment, supports computer resources, continues our efforts to improve the quality and throughput of electron microscopy data, and provides a sense of intellectual community and common identity for all the participants in the Program Project. PUBLIC HEALTH RELEVANCE: Our structural studies of several medically important protein complexes that play essential roles within the cell provide the basis for understanding their normal function as well as failures in these functions that are associated with disease and birth defects.